The G protein beta gamma subunits play a central role in signaling through their direct interactions with G protein a subunits, receptors, and effectors. This competing renewal application will examine the importance of G protein beta gamma subunit composition in specification of signaling pathways that regulate cardiac function. There are two major goals. First, we will investigate the basis for spatial and temporal expression of the y subunits as one factor defining specification among signaling pathways. Second, we will delineate the roles of the most divergent betaor gamma subunits in those signaling pathways that regulate cardiac chronotropy, inotropy, and growth. A gene targeting strategy, combined with biochemical, electrophysiological, and physiological analyses of embryonic stem cell and animal knockout models, will be used to identify signaling pathway(s) directly affected by gene disruption in a physiological context. Coupled with microarray analysis, these knockout models will also identify related or downstream gene products whose expression patterns are altered. Such studies will test the hypothesis that the G protein beta gamma dimers have unique roles in signaling pathways that regulate cardiac function and that their composition is an important determinant of the specificity of these pathways. Recent reports identifying a beta-3 subunit polymorphism in patients with essential hypertension, and other studies showing targeted inhibition of beta gamma dimers prevents vascular restenosis, suggest dysregulation or manipulation of these components may affect the progression of cardiac disease. Thus, studies of these knockout models will likely lead to elucidation of new therapeutic strategies for enhancing the function of the diseased heart.